Mycophenolic acid derivatives

ABSTRACT

Mycophenolic acid derivatives represented by the formula   WHEREIN R and R&#39;&#39; are as defined hereinafter, which are useful as an anti-cancer or anti-tumor agent and a process for the production thereof are disclosed.

United States. Patent [191 Mori et al.

[ MYCOPHENOLIC ACID DERIVATIVES [75] Inventors: Takasi Mori, Tokyo; Sakae Takaku, Ageo', Seikichi Suzuki, Tokyo, all of Japan Chugai Seiyaku Kabushiki Kaisha, Tokyo, Japan [22] Filed: Feb. 13, 1973 [21] Appl. No.: 332,102

[73] I Assignee:

[30] Foreign Application Priority Data OTHER PUBLICATIONS Wagner & Zook, Synthetic OrganieChemistry, New I Dec. 10,1974

York, Wiley and Sons, Inc., 1953, seam 41s relied on.

Primary Examiner-Donald G. Daus Assistant Examiner-Anne Marie T. Tighe Attorney, Agent, or FirmBrowdy and Neimark [57] ABSTRACT Mycophenolic acidderivatives represented by the formula OCOR' OH; (H)

CHziO- wherein R and R are as defined hereinafter, which are useful as 'an anti-cancerjor anti-tumor agent and a process for the production thereof are disclosed.

32 Claims, N0 Drawings l i MYCOPHENOLIC ACID DERIVATIVES BACKGROUND OF THE INVENTION H wherein R represents a lower alkyl group or a lower al- 7 kenyl-group; R is selected from the group consisting of wherein X is selected from the group consisting of a hy-' drogen atom, an'alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, an acyl group containing 2 to '5 carbon atoms, a halogen atom, an alkoxycarbonyl group containing 2 to 5 carbon atoms, an acylamino group containing 2 to 5 carbon atoms, a dialkylamino ethoxycarbonyl group containing S'to ,7 carbon atoms, a dialkylamino group containing 2 to 8 carbon atoms, a hydroxy group, acarboxy group, a sulfamoyl group, a nitro group, a cyano group and a phenyl group; X and Y may be the same or different and are selected from the group consisting of an alkyl group containing 1 to 4 carbon atoms, a hydroxy group, a carboxy group and a nitro group; and X is .selected from the group consisting of a hydrogen above fomrula (I) which are useful it; an anti-cancer or anti-tumor agent.

cess for the production. of mycophenolic acid deriva tives represented by the formula (I). These and other objects of this invention will be apparent by those skilled in the art by referring to the description given hereinafter. 3

DETAILED DESCRIPTION OF THE INVENTION In accordance with the process of this invention, the mycophenolic acid derivatives represented by the above formula (I) can be prepared by reacting a compound represented bythe formula o 0 OX3 ([1) wherein R is as defined above and X represents a halogen atom, with an amine compound of the formula (Ill) wherein R is as defined above.

The 1 compound represented by the formula (II) methoxyaniline, p-aminophenol, p-aminobenzoic acid,

atom, a halogen atom and a dialkylamino group containing2 to 8 carbon atoms.

2. Description of the Prior Art Mycophenolic acid is an antibiotic found in the fermentation broth of Penicillium brevi-compac'tum and is known to have weak growth inhibitory activityagainst' Gram-positive microorganisms, fungi and yeasts. Recently, attention has been drawn to the anti-cancer activity of mycophenolic acid in view of the fact that mycophenolic acid is found to have a potent inhibitory activity on the implanted tumor in a wide variety of anima] species. However, the therapeutic index of mycophenolic acid is notsaid to be satisfactory.

SUMMARY OF THE INVENTION An object of this invention is therefore to provide mycophenolic acid. derivatives represented by the p-am'inoacetophenone, m-chloroaniline, pchloroaniline, ethyl p-aminobenzoate, pacetylaminoaniline, p-aminobiphenyl, pdiethylaminoaniline, p-( 2'-diethylaminoethoxycarbonyl)-aniline, 3-nitro-4-methylaniline, dimethylaniline, 2-oxy-4-aminobenzoic acid, benzylamine, m-chlorobenzylamine, sulfanylamide, p- (diethylaminobenzyl)-amine, cyclohexylamine or. the

: solvent such as benzene, diethyl ether, tetrahydrofuran, dioxane, chloroform, methylene chloride, ethyl acetate, carbon tetrachloride or the like. The reaction temperature is not critical and is preferably in the rangeof to 30C, for a period of from 1 to 5 hours. The process of this invention is a reaction which releases an acid' of the formula HX, and, therefore, the reaction between the compound (II) and the amine (III) is preferably carried out in the presence of a tertiary amine such as triethylamine, pyridine, N,N-dimethylaniline, N-

' methylpyrolidine', Nmethylpiperidin e or the like or an inorganic base such as sodium' carbonate, potassium carbonate or the like. Alternatively, the reaction may be conducted by usingmore than two molar equiva-' 1 lents of the amine compound (111) per one molar equivtertiary amine or inorganic base. if the amine compound (Ill) carries any-reactive group other than the reactive moiety which takes part in the reaction of this invention, it is advantageous to carry out the reaction after protecting these reactive groups, if necessary. In the reaction for producing the mycophenolic acid derivatives (1), the desired compound (I) can be isolated from the reaction mixture by any one of the con-v ventional procedures, for example. by filtration of the reaction mixture followed by concentration of the filtrate or by extraction of the reaction mixture with an organic solvent followed by concentration of the extract. The thus obtained product can then be purified BDF, mice(body weight,-20 g i 2 g) were intraperi-- toneally implanted with 1 X cells/mouse of 1,121.0

, Table l-Continued Antiturnor Activity of Myco'phenolic Acid Derivatives Activity* Compound T/C in L-l2l0 T/C in Ehrlich Tumor Example l6 H: Example 17 -ll- Example 18 -H" -H-H- Example I) -li- Example 20 -l+l- -H- Example 2| -H-H- +H- Example 22 -llll-' ++l- Example 23 -i+++ -l+l- Example 24 -H+l -H- Example 25 +l-H- +H- Example 26 +-ll- -H+ Example 27 +H- -l+ Example 28 -Hl- -l+ Example 29 -l+l+ -H'- Example 30 +H- Example 31 -H-H- +H- Mycophenolic v v Acid -l- T/C in L-l2 10 T10 in Ehrlich Tumor +H-lhigher than L50 lower than 0.10 -Hl-- 1.40-1.49 O.ll-O.20' H- 130- 1.39 0.21- 0.30 0.3] 0.40

a day over a periodof 5 days. The survival period (days) of the test mice was determined, and the activity of the test compounds was evaluated in terms of T/C (an average survival day of the treated mice/an survival day of the non-treated mice).

Activity on Hypodermically Implanted Ehrlich Tumor I 4 cs mice (male; bodyweight, 20g :2 g) were hypo-- dermically implanted with 5 X 10 cells/mouse of Ehrlich ascites-tumor cells, and, 20 hours after the inocula; tion, eachof the test compounds was intraperitoneally administered to the mice at the dose of 150 mg/kg once a day over a period of'5 days. The tumor weight of the sacrificed mice was determined 10 days after the implantation, and the activity of the test compounds was evaluated in terms of T/C (the average tumor weight of the treated mice/the average tumor weight of the nontreated mice). y V In the above tests, the test compounds were used as a solution dissolved in distilled water or as a suspension inv distilled water containing 0.5% CMC.

The results obtained in the above experiments are shown in Table 1 below.

Table l Mycoph enolic Acid Derivatives Antitumor Activity of Activity Compound I I TIC inL-lZlO 17C in Ehrlich Tumor Example 7 Example l Example 2 Example 3 Example 4 Example 5 Example 6 Example 8 Example 9' Example 10 Examplell Example 12 Example 13 Example 14 Example l5 average It is apparent from the aboveresults that the compounds of this invention exhibit an antitumor activity the hypodemiically implanted Ehrlich tumor cells.

Example l Methyl 5-[4-(N,N Ethylenecarbamoyloxy)-6- Methoxy-7 '-Methyl 3 -Oxo-5 -Phthalanyl l-3-Methyl- 3-Pentene-1-Carboxylate A. About 100 g of phosgene was bubbled into 200 ml of dried benzene, and to the resulting solution was added dropwise a solution of 33.4 g of methyl myco phenolate and 7.91 g of pyridine in 100 ml of benzene over two hours while stirring at a temperature .of from 0C to 5C. After stirring at room temperature for an additional 10 hours, the mixture was filtered to remove pyridine hydrochloride, and the filtrate was concen-* slightly yellow-colored powdery solid and recrystallization of the crude product from ether yielded apure product having a melting point of from 80.5to 81 .5C.

3.396 g of the methyl 5-(4' chlor' oformyloxy-6'- methoxy-7'-methyl-3f-oxo-5'-phthalanyl)-3-methyl-3- pentenel -carboxylate obtained above was dissolved in 20 ml of tetrahydrofuran, and to the solution was added dropwise a mixture consisting of 0.41 g of ethylenimine, 0.98 g of triethylamine and 5 ml of tetrahydrofuran over 30 minutes at a temperature of 0C while stirring. After stirring for an additional '1 hour, 50 ml 1 of water was added to the mixture and the mixture was extracted with benzene. The benzene extract was washed with water, dried and concentrated under reduced pressure.- The resulting residue was recrystallized first from'a methanol-water solvent system and then from a benzene-hexane solvent system to obtain 2.9 g of a pure methyl ethylenecarbamoyloxy )-6 '-methoxy.-7 -methyl-3 -oxopentene- 1 -carboxy1ate having 'a melting point of 79.5C

B. In the same manner as described in Example 1, Part (B), ethyl 5-(4-chloroformyloxy-6-methoxy-7- methyl-3 '-oxo-5 '-phthalanyl )-3-methyl-3-pentenel carboxylate was-reacted with ethylenimine to obtain ethyl 5-[4'-(N,N-ethylenecarbamoyloxy)-6'-methoxy- 7 '-methyl-3 '-oxo-5 -phthalanyl ]-3-methyl-3-pentene- .l-carboxylate having a melting point of 78 79C. Analysis: C, 63.66; H, 6.44; N, 3.39 Example 3 n-Butyl 5-[4'-(N,N-Ethylenecarbamoyloxy)-6'- Methoxy-7-Methyl-3-Oxo-5-Phthalanyl]-3-Methyl- B-Pentene- 1 -Carboxylate A. In the same manner as described in Example 1, Part (A), butyl mycophenolate was reacted with phosgene to obtain n-butyl 5-(4'-chloroformyloxy-6'- methoxy-7 '-methyl-3 -oxo-5 '-phthalanyl )-3-methyl-3-- pentenel -carboxylate which was not easily crystallized and used directly in the next reaction.

B. In the same manner as described in Example 1, Part (B), n-butyl 5-(4-chloroformyloxy-6-methoxy-7'- methyl-3'-oxo-5'-phtha1anyl)-3-methyl-3-pentene- 1- carboxylate was reacted with ethylenimine toobtain n-butyl 5-[4-(N,N-ethylenecarbamoyloxy)-6- methoxy7-methyl-3-oxo-5phthalanyl]-3-methyl-3- pentene-l-carboxylate. The thus obtained product was a viscous oily substance which was not easily crystallized, and was purified by column chromatography using a powder cellulose. Analysis: C, 64.69; H, 6.80; N, 3.11

Example 4 Methoxy7 -Methyl-3 -Oxo-5 '-Phthalanyl ]-3-Methyl- 3-Pentene- 1--Carboxy1ate 2 g of ethyl 5-,(4-ch1oroformyl0xy-6-methoxy-7'- methyl-3'-oxo-5'-phthalanyl)-3-methy1-3-pentene-1- carboxylate was dissolved in 20 ml of tetrahydrofuran, and to the solution was added dropwise a solution of 1.51 g of p-aminoacetophenone in ml of tetrahydrofuran over 30 minutes at a temperature of 0C while stirring. After stirring for an additional 1 hour at room temperature, 50 ml of water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with lN-hydrochloric acid followed by with water, dried and concentrated. The resulting residue was recrystallized from ethanol to give 1 .5 g of ethyl 5-[4 -(p-acetylphenyl)-carbamoyloxy}-6'-methoxy-7'- methyl-3 '-oxo-5 '-phthalanyl ]-3-methyl-3-pentenel carboxylate having a melting point of 159 160C. Analysis: C, 66.21; H, 6.13; N. 2.83 Example 5 Methyl 5- 4 N-Phenylcarbamoyloxy )-6'-Methoxy- 7-Methyl-3-Oxo-5-Phthalanyl]-3-Methyl-3-Pentene l -Carboxylate 5 '-phthalany1l-3-methyl-3-pentenel -carboxylate hav- In the same manner as described in Example 4, methyl 5-(4-chloroformyloxy-6-rnethoxy-7-methyl- 3 -oxo-5 -phthalanyl )-3-methyl-3-pentene- 1 carboxylate was reacted with aniline to obtain methyl 3 '-oxo-5 -phthalanyl -3-methy1-3-pentenel carboxylate having a melting point of 1 15 116C. Analysis: C, 65.96; H, 5.84; N, 3.34 Example 6 Ethyl 5-[4'-{N-(p-Methylphenyl )-Carbamoyloxy} 6-Methoxy-7'-Methyl3'-Oxo-5-Phthalanyl -3- Methyl-3-Pentenel -Carboxylate In the same manner as described in Example 4, ethyl 5-(4'-chloroformyloxy-6'-methoxy-7'-methyl-3 '-oxo- 5 '-phthalanyl )-3-methyl-3-pentene- 1 -carboxylate was reacted with, p-toluidine to obtain 5-[4-{N-(pmethylphenyl )-carbamoyloxy} -6 -methoxy-7 -methyl- 3 -oxo-5 -phthalanyl -3-methyl-3-pentene- 1 carboxylate having a melting point of 985 995C.

Analysis: C, 67.41; H, 6.51; N, 3.00

Example 7 Ethyl 5- [4- i N-( p-Methoxyphenyl )-Carbamoyloxy} 6'-Methoxy-7 -Methyl-3 -Oxo-5 '-Phthalanyl 3- Methyl-3'-Oxo-5'-Phthalanyl]-3-Methy1-3- Pentene-l-Carboxylate In the same manner as described in Example 4, ethyl 5-( 4'-chloroformyloxy-6 '-methoxy-7 '-methyl-3 '-oxo- 5-phthalanyl-3-methyl-3-pentene-1-carboxylate was reacted with p-methoxyaniline to obtain ethyl 5-[4'- 1N-(p-methoxyphenyl)-carbamoyloxy}-6'-methoxy-7- methyl-3 -oxo-5 '-phthalanyl ]-3-methyl-3-pentene- 1 carboxylate having a melting point of 118 119C.

and to the solution was added dropwise a solution of g 1.7 g of p-aminobenzoic acid in 10 m1 of tetrahydrofuran over 20 minutes while ice-cooling and stirring. After stirring for an additional 3 hours at room temperature, ml of 0.1N-hydrochloric acid was added to the mixture, and the crystals which precipitated were filtered, washed with water and dried under reduced pressure. The thus obtained product was recrystallized from an ethanol-benzene-hexane solvent system to give 2.4 g of pure ethyl 5-[4-{N-(p-carboxyphenyl) carbamoyloxy} -6-methoxy-7'-methyl-3'-oxo- 5- phthalanyll-3-methyl-3-pentenel-carboxylate having a melting point of 186C (with decomposition;

' carboxylate having-a melting point of 1 165 --1 l7.5C.

Analysisz C, 62.00; H, 5.55; N, 7.88 Example 11 Ethyl -[4-{N-(p-Ethoxycarbonylphenyl)- Phthalanyl -3-Methyl-3-Pentene- 1 -Carboxylate In thesame manner as described in Example 4, ethyl 5 '-phthalanyl )-'3-methyl-3-pentene- 1 -carboxylate was reacted with-ethyl p-aminobenzoate to obtain ethyl 5- Y [4'- {N-( p-ethoxy-carbonylphenyl )-carbamoyloxy}-6'- methoxy-7 -methy1-3 '-oxo-'5 '-phtha1anyl l-3-methyl-3- pentene-l-carboxylate having a melting point of 448 Analysis: C, 64i26; H, 6.02; N, 2.44

Example 12 v i Ethyl 5-[4'-{N (p-Acetylaminophenyl)- Carbamoyloxy)-6-Methoxy-7 '-Methyl-3 '-Oxo-5 Phthalanyl]-3-Methyl-3-Pentene- 1 -Carboxylate In the same manner as described in Example 4, ethyl 5-(4-chloroformyloxy-6-methoxy-7'-methyl-3-oxo- 5 '-phthalanyl )-3-methyl-3-pentene- 1 -carboxylate was reacted with p-acetylaminoaniline to obtain 5-[4'-{N- (p-acetylaminnophenyl)-carbamoyloxy}-6-methoxy- 7'-methyl-3'-oxo-5'-phthalanyll-3-methyl-3-pentenel-carboxylate having a melting point of 175 177C. Analysis: C, 64.27; H, 6.08; N, 5.37 Example 13 Ethyl Ph'thalanyl ]-3-M'ethyl-3-Pentene- 1 -Carboxylate In the same manner as described in Example 4, ethyl 5-( 4 '-chloroformyloxy-6 '-methoxy-7 -methyl-3 '-0x0- 5 '-phthalanyl)-3-methyl-3-pentene- 1 -carboxylate was reacted with p-aminobenzenesulfonamide to obtain ethyl 5-[4 {N-(p-sulphamoylphenyl')-carbamoyloxy} 6 '-methoxy-7-methyl-3 '-oxo-S '-phthala.nyl ]-3 -methyl- 3-pentene-1-carb0xylate having a melting point of 150 153C.

Analysis: C, 57.28; H, 5.61; IN, 5.22

Example 14 Ethyl 5-[ 4 {N-(p-Phenyl-Phenyl )-Carbamoyloxy} 6-Methoxy:7' Met1 yl-3 '-Oxo-5'- Phthalanyl]-3- Methyl-3-Pentene- 1 -Carboxylate In the same manner as described in Example 4, ethyl 5-14-chloroformyloxy-6'-rnethoxy-7-methy1-3'-oxo- 5 -phthalanyl )-3-methyl-3-pentene- I-carboXylate was reacted with p-aminobiphenyl to obtain ethyl 5-[4'-{N- (p-phenyI-phenyl)-carbamoyloxy}-6'-methoxy-7'- methyl-3 '-oxo-5 '-.phthalany l ]-3-methyl-3 -penltene- 1- carboxylate having a melting point of 110 112C. Analysis: C, 70.83; H, 6.09; N, 2.44

Example 15 Ethyl 5-[4"-{N-(p-Diethylaminophenyl)- Carbamoyloxy} -6'-Methoxy-7-Methyl3 FOxo-S Phthalanyl -3-Methyl-3-Pentenel -Carboxylate drochloride 2.1 g of ethyl 5-(4'-chloroformyloxy-6-methoxy-7'* methyl-3'-oxo-5 '-phthalanyl )-3-methyl-3-pentenel carboxylatc was dissolved in 30 ml of chloroform, and t0 the solution was added dropwise a solution of 0.82 g of p-diethylaminoaniline in 10 ml of chloroform over 30 minutes at a temperature of 0C while stirring, followed by stirring for an additional 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was recrystalized from ethanol to give 2.3 g of ethyl 5-[4- {N-( p-diethylaminophenyl )-carbamoyloxy}-6 methoxy-7 '-methyl-3 '-oxo-5 '-phth alanyl -3-methyl-3- pentene-l-carboxylate hydrochloride having a melting Phthalanyl]-3-Mcthyl-3-Pentene-l-carboxylate point of 187 189C (decomposition).

Analysis: C, 62.71; H, 6.92; N, 4.86

Example 16 a Ethyl 5-[4'- {N-(p-(/3-Diethylaminoethoxycarbonyl phenyl )-Carbamoy1oxy}-6'-Methoxy-7 '-Methyl-3 Oxo-S '-Phthalanyl -3.-Methyl'-3-Pentenel Carboxylate Hydrochloride In the same manner as described in Example 15,

ethyl S-(4'-chloroformyloxy-6' methoxy-7-rnethyl-3'- oxo-S -phthala nyl) -3 -methyl.-3 -p'entene-1 carboxylate was reacted with p-(,B-diethylaminoethoxycarbonyl)- diethylaminoethoxycarbonyl )-phenyl )-carbamoyloxy} 6 '-methoxy-7 '-methyl-3 -oxo-5 '-phthalanyl -3-m ethyl- 3-pentene-1-carboxylate hydrochloride having a melting point of 146 148C (decomposition).

Analysis: C, 60.93; H, 6.53;. N, 4.34

Example 17 I Ethyl 5-[ 4'-{ N-( p-Dimethylaminophenyl Carbamoyloxy}-6-Meth oxy-7 '-Met hyl-3 -Oxo-5 Phthalanyl ]-3-Methyl- 3-Pentenel -Carboxylate drochloride In the same manner as described in Example 15,.

ethyl 5-( 4'-chloroformyloxy-6 -methoxy-7 '-methyl-3 oxo-5 '-phthalanyl )-3-methyl-3-pentene- 1 -carboxylate was reacted with N,N-dimethyl-p-phenylenediamine to obtain ethyl 5-[4'-{N-(p-dimethylaminophenyl)- carbamoyloxy} -6-methoxy-7 '-methy1-3 '-oxo-5 phthalanyl l-3-methyl-3-pentene- 1 -carboxylate hydrochloride having a melting point of 171 173C (decomposition). Analysis: C, 61.40; H, 6.79; N, 5.09 Example 18 i drochlon'de In the same manner as described in Example 15,.

oxo-S 'phthalanyl )-3methyl-3-pen tene-1-carboxy1ate was reacted with p-diethylaminobenzylamine to obtain ethyl 5-[4'-{N-(p-diethylaminobenzyl)- carbamoyloxy}-6 '-methoxy-7 '-meth'yl-3 '-oxo-5 phthalanyl ]-3-methyl-3-pentene- 1 -carboxylate hydrochloride having a melting point of 136 139C (decomposition). Analysis: C, 63.20; H, 6.71; N, 5.80 Example 19 Ethyl 5-[4l-{N-(p-Dimethylaminobcnlyn- Carbamoyloxy} -6 '-'Methoxy-7 "Methyl-3 -0xo-5 9 Phthalanyll-3-Methyl-3-Pentene-1-Carboxylate Hydrochloride 1n the same manner as described in Example 15, ethyl 5-( 4 'chloroformyloxy-6 '-methoxy-7 Fmethyl-3 oxo-S -phthalanyl 13-methyl-3-pentene- 1 -carbxylate was reacted with p-dimethylaminobenzylamine to obtain ethyl -[4'-{N-(p-dimethylaminobenzyl) carbamoyloxy} -6'-methoxy-3 -methyl-3 '-oxo-5 phthalanyl -3-methyl-3-pentene- 1 -carboxylate hydrochloride having a melting point of 123 125C (de- Composition).

Analysis: C, 62.24; H, 6.71; N, 5.08 Example n-Butyl 5-[4'-{N-(p-Carboxyphenyl)- Carbamoyloxy}-6'-Methoxy-7-Methyl-3-Oxo-5'- Phthalanyl -3-Methyl-3-Pentene- 1 -Carboxylate In the same manner as described in Example 9, nbutyl 5-( 4 '-chloroformyloxy )-6 -methoxy-7 '-methyl- 3-oxo-5phthalanyl)-3-methyl-3-pentene-1- carboxylate was reacted with p-aminobenzoic acid to obtain n-butyl 5-[4'-{N-(p-carboxyphenyl)- carbamoyloxy}-6'-methoxy-7-methyl-3-oxo-5- phthalanyl l-3-methyl-3-pentene- 1 -carboxylate having a melting point of 177 180C (decomposition). Analysis: C, 64.65; H, 6.14; N, 2.53 Example 21 Ethyl 5-[4-(N-Phenylcarbamoyloxy)l6'-Methoxy- 7'-Methyl-3-Oxo-5'-Phthalanyll-3-Methyl-3-Pentenel-Carboxylate In the same manner as described in Example 4, ethyl 5-(4'-chlorofonnyloxy-6-methoxy-7'-methyl-3'-oxo- 5 -phthalanyl )-3-methyl-3-pentenel -carboxylate was reacted with aniline to obtain ethyl 5-[4'-(N- phenylcarbamoyloxy)-6'-methoxy-7'-methyl-3'-oxo- 5 '-phthalanyl )-3-methyl-3-pentenel -carboxylate having a melting point of 117 119C.

Analysis: C, 66.80; H, 6.21; N, 3.31 Example 22 Ethyl 5-[4'-{N-(m-Nitrophenyl)-Carbamoyloxy}-6- Methoxy-7 '-Methyl-3 '-Oxo-5 '-Phthalanyl -3-Methyl- 3-Pentene-Carb0xylate 1n the same manner as described in Example 4, ethyl 5-94'-chloroformyloxy-6' methoxy-7'-methyl-3-oxo 5 '-phthalanyl )-3-methyl-3-pentenel-carboxylate was reacted with m-nitroaniline to obtain ethyl 5-[4'-{N- (m-nitrophenyl )-carbamoyloxy} -6-methoxy-7 methyl-3 -oxo-5 -phthalanyl ]-3-methyl-3-pentene- 1- carboxylate having a melting point of 149 150C. Analysis: C, 60.92; H, 5.53; N, 5.62 Example 23.

. 10 5 'phthalanyl )-3-methyl-3-pentene- 1-carboxylate was reacted with m-toluidine to give ethyl 5[4'-'{N-(mmethylphenyl)-carbamoyloxy}-6"methoxy-7'-methyl- 3 '-ox0-5 '-phtha1anyl ]-3-methyl-pentenel-carboxylate having a melting point of 98 100C- Analysis: C, 67.09; H, 6.48; N, 2.93 Example 25 Ethyl 5- 4'- {N-(m-Chlorophenyl )-Carbamoyloxy} 6'-Methoxy-7 '-Methyl-3 '-Ox0-5 '-Phthalanyl ]-3- Methyl-3-Pentene- 1 -Carboxylate In the same manner as described in Example 4,ethyl 5-( 4 "-chloroformyloxy--meth0xy-7 -methyl-3 '-ox0- 5 'phthalanyl )-3-methyl-3-pentenel-carboxylate was reacted with m-chloroaniline to give ethyl 5-[4-{N- (m-chlorophenyl)-carbamoyloxy}-6'-methoxy-7'- methy1-3 '-oxo-5 -phthalanyl ]-3-methyl-3-pentenel carboxylate having a melting point of 102 103C.

'- Analysis: C, 61.88; H, 5.46; N, 2.78

Example 26 Ethyl 5-[4'-{N-(3"-Nitro-4"-Methylphenyl)- Carbamoyloxy}-6 '-Methoxy-7 -Methyl-3 '-Oxo-5 g Phthalanyl -3-Methyl-3-Pentenel-Carboxylate In the same'manner as described in Example 4, ethyl 5-(4-chloroformyloxy-6'-methoxy-7 -methyl-3 '-oxo- 5 -phthalanyl )-3-methyl-3-pentene- 1 -carboxylate was reacted with 3-nitro-4-methylaniline to give ethyl 5 [4'- {N-(3l-nitro-4"-methylphenyl)-carbamoyloxy}-6'- methoxy-7 -methyl-3 '-0xo-5 -phthalanyl -3-methyl-3- pentene-1- carboxylate having a melting point of 142 143C. Analysis: C. 61.1 1; H, 5.64; N, 5.29

Example 27 y Ethyl 5-[4-{ N-(2",4"-Dimethylphenyl)- Carbamoyloxy }-6'-Methoxy-7 '-Methyl-3 '-Oxo-5 Phthalanyl ]-3-Methyl-3-Pentene 1 -Carboxylate 1n the same manner as described in Example 4, ethyl 5-(4'-chloroformyloxy-6-methoxy-7 '-methyl-3 '-0xo- 5 -phthalanyl )-3-methyl'-3-pentenel -carboxylate was reacted with 2,4-dimethylaniline to give 5-[4'-{N- carboxylate was dissolved in 30 ml of tetrahydrofuran,

and to the solution was added 1.53 g of 2-oxy-4 aminobenzoic acid. The mixture was then stirred ina sealed vessel at room temperature. After 3 hours reaction, ml of water was added to the reaction mixture which was then extracted with chloroform. The chloroform layer was washed with lN-hycrochloric acid followed by rinsing with water, dried and concentrated. The residual yellow oil thus obtained was dissolved in ether and the solution was allowed to stand to precipitate 1.9 g of ethyl 5-[4'-{N-(3"-0xy-4"- carboxyphenyl)-carbamoyloxy}-6-methoxy-7- rnethyl3 -oxo-5 :phthalanyl]-3 -methyl-3 -pentene'-"l carboxylate as white crystals having a melting point of 183 185C (decomposition). Analysis: C, 61.77; H, 5.64; N, 2.58

'Example 29 Ethyl -[4' (NBenzylcarbamoyloxy)-6'-Methoxyv 7 -Methyl-3 -Qxo-5 '-Phthalanyl ]-3-Methyl-3-Pentene- 5-(4'-chloroformyloxy-6'-methoxy-7-methyl-3-oxo- 5 '-phthalanyl )-3-methyl- 3-pentenel -carboxylate was reacted with m-chlorobenzylamine to give ethyl 5-[4'- methyl-3 '-oxo'-5 'phthalanyl l-3-methyl-3-pentenel carboxylate having amelting point of 122 123C.

Analysis: C, 62.71; H, 5.99; N, 2.74

Methoxy-7 '-Methyl-3 '-Oxo-5 '-Phthalanyl -3-Methyl- 3 -Pentenel Carboxylate 1 ,12. thoxycarbonyl having 5 to 7 carbon, atoms, dialkylamino -having 2 to 8 carbon atoms, hydroxy, carbox'y,

sulfamoyl, nitro, cyano and phenyl; X and Y are the same or different and are selected from the group con- 'sisting of alkyl having 1 to 4 carbon atoms, 'hydroxy,

carboxy and nitro; X is selected from the group consisting of hydrogen, chlorine, and dialkylamino having 2 to 8 carbon atoms.

2. Methyl 5-[4'-(N,N-ethylenecarbamoyloxy)-6'- meth0xy-7 -methyl-3 '-oxo-5 '-phthal anyl ]-3.-me'thyl- 3 penten'e-lcarboxylate in accordancewith claim 1.

3. Ethyl 5-[4'-(N,N ethylenecarbamoyloxy)-6'- methoxy-7'-methyl-3'-oxo-5'-phthalanyl]-3-methyl-3- pentene-l-carboxylate in accordance with claim I. e 4.- Butyl methoxy-7 '-methyl-3 -oxo-5 '-phthalanyl ]-3-methyl--3- pentene-l-carboxylate in accordance with claim 1.

3-pentene-l-carboxylate in accordance with claim 1. Methyl methoxy-,7'-methyl-3'-oxo-5'-phthalanyl]-3-methyl-3- pentene-l-carboxylate in accordance with claim 1.

In the same manner as described in Example 4, ethyl phthalanyl 3-methyl-3-pentenel {carboxylate was reacted with cyclohexylamine to give ethyl 5-[4"-(N- cyclohexylcarbamoyloxy)-6'-methoxy-7' methyl-3'- oxo-5 '-phthalanyl 3-methyl-3-pentenel -carboxylate having a melting point of 143 144C.

Analysis: C, 65.90; H, 7.20; N, 3.00

While the invention has been described in detail and 4 with reference to specific embodiments thereof, it will,

be apparent that various changes and modifications can scope thereof.

What is claimed is: l. a compoundof the formula:

be made therein without, departing from the spirit and wherein represents lower alkyl; R' is selected from the group consisting of wherein is selected from the group consisting of hydrogen, alkyl having I to .4 carbon atoms alk'oxy having 1 to 4carbon atoms, R"COwherein R" is'alkyl having 1 to 4 carbon atoms, chlorine group containing 2 m5 carbon atoms, a halogen atom, alkoxy-carboxyl having 2 to 5 carbon atoms, R"CONl-l -"-wherein- R" "is alkyl having 1 to carbon atoms, dialkylaminoe- I cordance with claim 1.

6methoxy-7 '-m ethyl-3 '-ox0-5 '-phthalanyl l-3-methyl- 3-pentene-l-carboxylate in accordance with claim: 1.

8. Ethyl carbamoyloxy}-6'-methoxy 7'-methyl-3'-Qxo-5'- phthalanyll-3-methyl-3-pentene-l-carboxylate in ac- 9.. Ethyl carbamoyloxy} -6 -methoxy-7 -methyl-3 '-oxo-5 phthalanyl]-3-methyl-3-pentene-l-carboxylate in ac-' cordance with claim 1.

10. Ethyl a amali qaxli6ffmthoxy h l- 0x91 7- phthalanyl]-3-methyl-3-pentene-l-carboxylate ina ccordance with claim 1.. I -1l. Ethyl 5-[4-{N-(p-chlorophenyl)- carbamoyloxylj-6-methoxy-7 -methyl-3 '-oxo-5 phthalanyl]'3-methyl-3-pentene-l-carboxylate in accordance with claim 1. r

-12. .Ethyl :-.5 [4-{N-(p-ethoxycarbonylphenyl)- carbar'noyloxy} -6-methoxy-7 methyl-3 '-oxo'-5 phthalanyl1-3-methyl-3-pentene-l carboxylate in accordance with claim 1.

13. Ethyl 5-[4'-{N-(p-acetylaminophenyl)- carbamoyloxy}-6 '-methox y-7 '-methyl-3 -oxo-5 phthalanyl]- 3-methyl-3-penteneal-carboxylate in accordance with claim 1.

14.. Ethyl v.5-[4-{N-(p-sulfamoylphenyl)- carbarnoyloxy}-6-methony-7f-methyl 3"-oxo-5- phthalanyl ]-3-methyl-3-pentenel -carboxylate in, ac-

15. Ethyl carbamoyloXyl-6 '-methoxy-7 '-methyl-3 -oxo-5 phthalanyl]-3-methyl-3-pentene-l-carboxylate in accordance with claim 1.

l6. Ethyl carbamoyloxy} -6'-methoxy-7 '-methyl-3 -oxo-5 phthalanyl l-3-methyl-3-pentenel -carboxylate in accordance with claim 1.

l7. Ethyl 5 [4-lN-(p w-diethylaminoethoxy)- carbonylphenyl)-carbamoyloxy}-6'-methoxy-7'- methyl-3'=oxo-5' phthalanyll-3-methyl-3-pentene-lcarboxylate in accordance with claim 1.

UNITE-D STATES PATENT OFFICE CERTIFICATE OF CORRECTION Dated December l0, 1974 Takasi Mor'i et a1.

, "21.1" should read --2.l--

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby correctedas shown below:

second column, line 10, "l-H+i" should read --+4++-- should read --Methoxy-7'Methyl--3' -Oxo'-5' Phthalanyl]--3Methyl'- the formula should read:

- -n-butyl 5-(4'-chloroformyloxy -6' -methoxy-4 insert --N-- before (-p-acetylphenyl) "7-Methyl-3'fl should read --7'--Methyl3' insert after "Phthalanyl should read -Methyl-3- insert after "-phthalanyl" should read --Carbamoyloxy}6' -Me.thoxy--7'- Methyl3'-Oxo5' "448" should read '-148 "IN" should read --N- should read -oxo-5'phthalanyl)-3-methyl-r pentenel-carboxylate-- should read --Ethyl 5-[4'-(N-Phenylcarbamoyloxy)-6'Methoxyshould read --5-(4'-chloroformyloxy-6 -methline 1, should read --Ethyl- 5 [N-{N-(phydroxyphenyl) Signed and gcaled this eleventh Of November 1975 Patent No. 5 Q

Inventor-(s) 4 Column 3, Table 1,

Column 5, line 24,

d line 33,

line 60,

line 67,

Column 6, line 11, line 26, line 42, (101mm 7, line 19, Di

line 27, line 55,

Column 9, line 5,

line 27,

line 43,

I Column 10, line 49 Column 12, claim 9,

{SEAL} Arrest:

RUTH C. MASON lmsting Officer 

1. A COMPOUND OF THE FORMULA:
 2. Methyl 5-(4''-(N,N-ethylenecarbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5''-phthalanyl) -3-methyl-3-pentene-1- carboxylate in accordance with claim
 1. 3. Ethyl 5-(4''-(N,N-ethylenecarbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5''-phthalanyl) -3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 4. Butyl 5-(4''-(N,N-ethylenecarbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5''-phthalanyl) -3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 5. Ethyl 5-(4''-(N-(p-acetylphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 6. Methyl 5-(4''-(N-phenylcarbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5''-phthalanyl)-3 -methyl-3-pentene-1-carboxylate in accordance with claim
 1. 7. Ethyl 5-(4''-(N-(p-methylphenyl)-carbamoyloxy)-6''@methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 8. Ethyl 5-(4''-(N-(p-methoxyphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 9. Ethyl 5-(4*-(N-(p-hydroxyphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 10. Ethyl 5-(4''-(N-(p-carboxyphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 11. Ethyl 5-(4''-(N-(p-chlorophenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 12. Ethyl 5-(4''-(N-(p-ethoxycarbonylphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo -5''-phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 13. Ethyl 5-(4''-(N-(p-acetylaminophenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methy13-pentene-1-carboxylate in accordance with claim
 1. 14. Ethyl 5-(4''-(N-(p-sulfamoylphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 15. Ethyl 5-(4''-(N-(p-phenylphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 16. Ethyl 5-(4''-(N-(p-diethylaminophenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5''-phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 17. Ethyl 5-(4''-(N-(p-( Beta -diethylaminoethoxy)-carbonylphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3'' -oxo-5''-phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 18. Ethyl 5-(4''-(N-(p-dimethylaminophenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo -5''-phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 19. Ethyl 5-(4''-(N-(p-diethylaminobenzyl)-carbamoyloxy)- 6''-methoxy-7''-methyl-3''-oxo-5''-phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 20. Ethyl 5-(4''-(N-(dimethylaminobenzyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 21. Butyl 5-(4''-(N-(p-carboxyphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 22. Ethyl 5-(4''-(N-phenylcarbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5''-phthalanyl)-3 -methyl-3-pentene-1-carboxylate in accordance with claim
 1. 23. Ethyl 5-(4''-(N-(m-nitrophenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 24. Ethyl 5-(4''-(N-(p-cyanophenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 25. Ethyl 5-(4''-(N-(m-methylphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 26. Ethyl 5-(4''-(N-(m-chlorophenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 27. Ethyl 5-(4''-(N-(3''''-nitro-4''''-methylphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3'' -oxo-5''-phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 28. Ethyl 5-(4''-(N-(2'''',4''''-dimethylphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo -5''-phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with cliam
 1. 29. Ethyl 5-(4''-(N-(3''''-oxy-4''''-carboxyphenyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3'' -oxo-5''-phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 30. Ethyl 5-(4''-(N-benzylcarbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5''-phthalanyl)-3 -methyl-3-pentene-1-carboxylate in accordance with claim
 1. 31. Ethyl 5-(4''-(N-(m-chlorobenzyl)-carbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5'' -phthalanyl)-3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 32. Ethyl 5-(4''-(N-cyclohexylcarbamoyloxy)-6''-methoxy-7''-methyl-3''-oxo-5''-phthalanyl) -3-methyl-3-pentene-1-carboxylate in accordance with claim
 1. 